Dr Viansone on Balancing ADCs and Low-Toxicity Chemotherapy in HER2+ Breast Cancer

“When we have chemotherapy that [is] not as toxic as ADCs, we can maintain the chemotherapy.”

Alessandro A. Viansone, MD, a medical oncologist at Gustave Roussy and part of the Gustave Roussy Alumni Network, discussed how the phase 2 PHERGain-2 trial (NCT04733118) could push HER2-positive breast cancer de-escalation further with antibody-drug conjugates (ADCs), and why the toxicity of an ADC such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) must be weighed against well-tolerated options, such as weekly paclitaxel.

PHERGain-2, a multicenter, single-arm, study, tested a pathologic complete response (pCR)–guided, chemotherapy-free strategy in selected patients with node-negative, HER2-positive early breast cancer and tumors measuring 5 to 30 mm. Patients received neoadjuvant subcutaneous trastuzumab (Herceptin) and pertuzumab (Perjeta); after surgery, those achieving a pCR continued antibody therapy, whereas those with residual disease were escalated to receive the ADC ado-trastuzumab emtansine (T-DM1; Kadcyla). The investigational strategy produced a pCR rate comparable with that seen with chemotherapy plus trastuzumab-pertuzumab and preserved health-related quality of life.

For Viansone, the PHERGain-2 results suggest that treatment de-escalation could go even further than initially proposed, noting that for a small amount of residual cancer, chemotherapy might be withheld in favor of proceeding directly to an ADC. He characterized the trial as a hypothesis generator for ADC-based, chemotherapy-sparing strategies in this setting.

In his view, the most effective ADC currently available is T-DXd, and future strategies might treat even small HER2-positive tumors directly with T-DXd rather than with weekly paclitaxel and trastuzumab, Viansone said. He acknowledged that this remains forward-looking; T-DXd is not currently established in stage I HER2-positive disease, where de-escalation is the prevailing approach.

The key consideration is toxicity, Viansone noted. Weekly paclitaxel is a chemotherapy with a favorable tolerability profile and has limited effect on quality of life, even over a 3-month course, whereas subcutaneous trastuzumab adds little burden, he explained. ADCs, by contrast, are associated with toxicities like fatigue and alopecia, according to Viansone. Swapping a well-tolerated chemotherapy for an ADC is therefore not automatically an improvement in the treatment paradigm, he said.De-escalation with ADCs is promising, Viansone concluded, but where an effective, low-toxicity chemotherapy such as weekly paclitaxel already provides good de-escalation, defaulting to an ADC may not always be the optimal choice.